Methods for biomedical targeting and delivery and devices and systems for practicing the same

ABSTRACT

The present disclosure provides methods for targeting a biomedical system. Aspects of the subject methods include determining the trajectory of a targeting device using magnetic resonance imaging (MRI) of a MRI-visible style of a trajectory guide that is compatible with the targeting device. Targeted biomedical systems may be utilized for a variety of purposes including targeted delivery of a therapeutic, holding a therapeutic device, positioning of a therapeutic device and other uses. Also provided are devices and systems that can be used in practicing the described methods including but not limited to trajectory guides and adjustable targeting systems, as well as non-transitory computer readable medium storing instructions that, when executed by a computing device, cause a computing device to perform steps of the described methods.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT/US2017/049191, filed Aug. 29,2017, which claims the benefit of U.S. Provisional Patent ApplicationNo. 62/381,423, filed Aug. 30, 2016, which application is incorporatedherein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant No. P01CA118816 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND

Many biomedical applications using advanced drugs and therapeutictechniques still require that the drug be delivered or the therapy beapplied to a precise location within the subject. Thus, propertherapeutic targeting remains an important aspect of many therapeuticprocedures regardless of treatment modality.

Exemplary areas of biomedicine where precise targeting is advantageousinclude neurological medicine and neurosurgery. For example, treatmentof central nervous system disorders can be challenging due to theprotected compartmentalization of the brain and spinal cord by theblood-brain barrier. In many circumstances, microinjections into thebrain parenchyma are important procedures to deliver drugs, viralvectors or cell transplants. Many brain diseases remain under treatedbecause of a lack of sufficiently precise and easy to use braintargeting systems that can efficiently assist a healthcare provider indelivering a therapeutic agent locally to the disease site in the brainwhile minimizing residual damage to surrounding brain structures.Besides agent delivery, neuroablation within the brain and intracranialsurgery facilitates the treatment of debilitating neurological disorderscharacterized by malfunctioning neurons such as epilepsy and malignanttissue such as brain tumors. Like precise agent delivery, thesetechniques require a high level of accuracy to be effective.

The benefit of precise targeting of therapeutic interventions is notlimited to neurological disorders and may include essentially anytreatment paradigm where the location of the affected tissues or theorigin of disease producing cells is known.

SUMMARY

The present disclosure provides methods for targeting a biomedicalsystem. Aspects of the subject methods include determining thetrajectory of a targeting device using magnetic resonance imaging (MRI)of a MRI-visible style of a trajectory guide that is compatible with thetargeting device. Targeted biomedical systems may be utilized for avariety of purposes including targeted delivery of a therapeutic,holding a therapeutic device, positioning of a therapeutic device andother uses. Also provided are devices and systems that can be used inpracticing the described methods including but not limited to trajectoryguides and adjustable targeting systems, as well as non-transitorycomputer readable medium storing instructions that, when executed by acomputing device, cause a computing device to perform steps of thedescribed methods.

Aspects of the present disclosure include a method of magnetic resonanceimaging (MRI)-assisted targeting of a desired area of a subject, themethod comprising: positioning an adjustable turret comprising a channelon a tissue surface of a subject; inserting a MRI-visible style of atrajectory guide within the channel of the adjustable turret;visualizing the MRI-visible style using an MRI imager; determining thetrajectory of the channel based on the visualizing; and adjusting theadjustable turret based on the determined trajectory of the channel totarget the desired area of the subject.

In some embodiments the adjustable turret is positioned ex vivo. In someembodiments, the method further comprises affixing a base to the tissuesurface of the subject and mounting the adjustable turret to the base.In some embodiments, the base is positioned ex vivo. In someembodiments, the base comprises a flange and the affixing comprisesmounting a fastener through the flange to affix the base to the tissuesurface of the subject. In some embodiments, the method furthercomprises locking the adjustable turret in place following theadjusting. In some embodiments, the locking comprises tightening alocking collar to compress the adjustable turret between the lockingcollar and the base. In some embodiments, the locking comprisestightening a locking collar to compress the adjustable turret between aplurality of annular walls of the base. In some embodiments, the channelis not coaxial with the turret. In some embodiments, the adjustingcomprises a roll adjustment relative to the long axis of the adjustableturret. In some embodiments, the adjusting comprises an angle adjustmentrelative to the long axis of the adjustable turret. In some embodiments,the adjustable turret comprises a plurality of channels. In someembodiments, the trajectory guide comprises a plurality of MRI-visiblestyles. In some embodiments, the trajectory guide has the same number ofstyles as the adjustable turret has channels.

Aspects of the present disclosure include a method of magnetic resonanceimaging (MRI)-assisted delivery of an agent or an electrical current toa desired area of a subject, the method comprising: targeting thedesired area of the subject according to any of the methods describedabove; removing the MRI-visible style from the channel following theadjusting; and delivering the agent or the electrical current throughthe channel to the desired area of the subject.

In some embodiments, the method comprises MRI-assisted delivery of anagent and the delivering comprises inserting a delivery devicecontaining the agent into the channel. In some embodiments, the deliverydevice comprises a needle or cannula. In some embodiments, the agent isa gene therapy vector. In some embodiments, the delivery devicecomprises a depth stop positioned at a point along the length of thedelivery device to prevent inserting the delivery device into thechannel past said point. In some embodiments, the method comprisesMRI-assisted delivery of an electrical current and the deliveringcomprises inserting an electrode into the channel. In some embodiments,the electrode comprises a depth stop positioned at a point along thelength of the electrode to prevent inserting the electrode into thechannel past said point.

Aspects of the present disclosure include a method of magnetic resonanceimaging (MRI)-assisted delivery of an agent or an electrical current toa desired area of a subject, the method comprising: positioning anadjustable turret comprising a plurality of channels on a tissue surfaceof a subject; inserting each of a plurality of MRI-visible styles of atrajectory guide within each of the plurality of channels of theadjustable turret;

visualizing the plurality of MRI-visible styles using an MRI imager;determining the trajectory of two or more channels of the plurality ofchannels based on the visualizing; identifying a channel of the two ormore channels with the trajectory closest to the desired area of thesubject; and delivering the agent or the electrical current through thechannel with the trajectory closest to the desired area of the subject.

In some embodiments, the method further comprises adjusting theadjustable turret based on the determined trajectory of the identifiedchannel to target said channel to the desired area of the subject.

Aspects of the present disclosure include a trajectory guide formagnetic resonance imaging (MRI)-assisted targeting of a desired area ofa subject, comprising: a solid support comprising a flat surface; aMRI-visible style comprising a lumen comprising a contrast agent,wherein the MRI-visible style is affixed at one end to the flat surfaceand dimensioned for insertion into a channel of an adjustable turretaffixed to a tissue surface of a subject thereby allowing targeting ofthe channel by visualizing the trajectory of the inserted MRI-visiblestyle using an MRI imager.

In some embodiments, the trajectory guide comprises a plurality ofMRI-visible styles. In some embodiments, the plurality of MRI-visiblestyles comprises two or more styles that are affixed symmetrically tothe flat surface with respect to the geometric center of the flatsurface. In some embodiments, the plurality of MRI-visible stylescomprises at least one style that is affixed asymmetrically to the flatsurface with respect to one or more styles of the plurality. In someembodiments, at least one MRI-visible style is affixed perpendicular tothe flat surface. In some embodiments, at least one MRI-visible style isaffixed at a flared angle to the flat surface. In some embodiments, thesolid support comprises an opening, opposite the flat surface, adjoininga void within the solid support that is contiguous with the lumen of theMRI-visible style thereby allowing access to the void and the lumen. Insome embodiments, the trajectory guide further comprises a cap forclosing the opening. In some embodiments, the cap and the openingcomprise compatible threading. In some embodiments, the contrast agentcomprises gadolinium.

Aspects of the present disclosure include, an adjustable targetingsystem, the system comprising: an adjustable turret comprising a distalend, a spherical end and one or more channels running from the distalend to the spherical end; a base, comprising: a plurality of annularwalls forming a socket dimensioned to receive the spherical end,threading on an external surface of the annular walls; a plurality ofslots positioned between the plurality of annular walls; and a flangeorthogonal to at least one of the annular walls for affixing the base toa tissue surface of a subject; and a locking collar comprising threadingon an internal surface compatible with the threading on the externalsurface of the base, wherein turning the locking collar a firstdirection compresses the spherical end to lock the adjustable turret ina desired trajectory and turning the locking collar a second directiondecompresses the spherical end to allow for retargeting of thetrajectory of the adjustable turret.

In some embodiments, turning the locking collar the first directioncompresses the spherical end between the base and the locking collar tolock the adjustable turret in a desired trajectory. In some embodiments,turning the locking collar the first direction compresses the sphericalend between the plurality of annular walls of the socket to lock theadjustable turret in a desired trajectory. In some embodiments, theadjustable targeting system is configured such that when affixed to thetissue surface of the subject the base and the locking collar are exvivo. In some embodiments, the adjustable targeting system is configuredsuch that when affixed to the tissue surface of the subject theadjustable turret is ex vivo. In some embodiments, the spherical endcomprises a flat portion opposite the distal end that comprises openingsto the one or more channels. In some embodiments, the spherical end andthe flat portion are dimensioned such that, when inserted into thesocket, the flat portion is flush with the bottom surface of the base.In some embodiments, the locking collar comprises a knurled externalsurface to provide grip. In some embodiments, the base comprises aplurality of flanges orthogonal to at least one of the annular walls. Insome embodiments, the system further comprises a trajectory guideaccording to any of those described above. In some embodiments, thesystem further comprises an MRI imager positioned to image a MRI-visiblestyle of the trajectory guide when the MRI-visible style is insertedinto a channel of the adjustable turret.

Aspects of the present disclosure include an adjustable targeteddelivery system, the system comprising: an adjustable targeting systemaccording to any of those described above; and a delivery device orelectrode dimensioned for insertion into the one or more channels of theadjustable turret.

In some embodiments, the delivery device or electrode comprises a depthstop positioned at a point along the length of the delivery device orelectrode to prevent inserting the delivery device into the one or morechannels past said point.

Aspects of the present disclosure include, a non-transitory computerreadable medium storing instructions that, when executed by a computingdevice, cause the computing device to perform the steps of: receiving amagnetic resonance image (MRI) of a trajectory guide MRI-visible styleinserted within a channel of an adjustable turret; determining thetrajectory of the channel based on the received MRI; comparing thedetermined trajectory to a desired user input trajectory; calculating arecommended adjustment of the adjustable turret necessary to align thedetermined trajectory with the desired user input trajectory based onthe comparing; and displaying the recommended adjustment.

Aspects of the present disclosure include an automated adjustabletargeting system, the system comprising: an adjustable targeting systemaccording to those described above; an actuator connected to theadjustable turret and controlled by a processor programmed withinstructions that, when executed by the processor, cause the processorto: determine the trajectory of a channel of the adjustable turret basedon a received magnetic resonance image (MRI) of a trajectory guideMRI-visible style inserted within the channel; compare the determinedtrajectory to a desired user input trajectory; calculate an adjustmentof the adjustable turret necessary to align the determined trajectorywith the desired user input trajectory based on the comparing; andtrigger the actuator to execute the adjustment thereby aligning thedetermined trajectory with the desired user input trajectory.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a method of targeting a device to a desired regionaccording to an embodiment described herein.

FIG. 2 depicts a method of targeting a device to a desired region whileavoiding an obstacle according to an embodiment described herein.

FIG. 3 depicts channel selection of a multi-channel targeting deviceaccording to an embodiment of the method described herein.

FIGS. 4A-4F provide exemplary arrangements of channels within a turretor styles of a trajectory guide as described herein.

FIGS. 5A-5B depict targeting device turrets having parallel andnonparallel channels.

FIGS. 6A-6B depict a targeting guide and a cutaway thereof according toan embodiment described herein.

FIGS. 7A-7B depict a targeting guide having a plurality of MRI-visiblestyles according to an embodiment described herein.

FIGS. 8A-8B depict adjustable turrets of a targeting device as describedherein.

FIGS. 9A-9B depict an assembled and unassembled multi-componenttargeting device as described herein.

FIG. 10 depicts a base of a multi-component targeting device asdescribed herein.

FIG. 11 depicts a cap configured for attachment to a base of amulti-component targeting device as described herein.

FIG. 12 depicts an adjustable turret of a targeting device having anasymmetry groove.

FIG. 13 depicts a trajectory guide and targeting device system accordingto an embodiment described herein.

FIGS. 14A-14C depict an assembled ex vivo targeting system according toan embodiment described herein.

FIGS. 15A-15B depict a targeting system, as described herein, having abase with an in vivo portion.

FIG. 16 depicts a targeting system as described herein.

FIG. 17 depicts a targeting system as described herein.

FIG. 18 provides a flowchart demonstrating the movement through atargeting system process as described herein.

DEFINITIONS

As used herein, “treatment” or “treating” refers to inhibiting theprogression of a disease or disorder, or delaying the onset of a diseaseor disorder, whether physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. As used herein, the terms “treatment,” “treating,” and thelike, refer to obtaining a desired pharmacologic and/or physiologiceffect. The effect may be prophylactic in terms of completely orpartially preventing a disease or condition, or a symptom thereof and/ormay be therapeutic in terms of a partial or complete cure for a diseaseor disorder and/or adverse effect attributable to the disease ordisorder. “Treatment,” as used herein, covers any treatment of a diseaseor disorder in a mammal, such as a human, and includes: decreasing therisk of death due to the disease; preventing the disease of disorderfrom occurring in a subject which may be predisposed to the disease buthas not yet been diagnosed as having it; inhibiting the disease ordisorder, i.e., arresting its development (e.g., reducing the rate ofdisease progression); and relieving the disease, i.e., causingregression of the disease. Therapeutic benefits of the present inventioninclude, but are not necessarily limited to, reduction of risk of onsetor severity of disease or conditions associated with neurologicalconditions.

The term “assessing” includes any form of measurement, and includesdetermining if an element is present or not. The terms “determining”,“measuring”, “evaluating”, “assessing” and “assaying” are usedinterchangeably and include quantitative and qualitative determinations.Assessing may be relative or absolute.

The term “inputting”, as used herein, is used to refer to any way ofentering information into a computer, such as, e.g., through the use ofa user interface. For example, in certain cases, inputting can involveselecting a target or trajectory that is already present or identifiedon a computer system. In other cases, inputting can involve target ortrajectory to a computer system, e.g., by defining a target ortrajectory on an image within the computer system with or without firstgenerating the image on a device capable of interfacing with a computer.As such, inputting can be done using a user interface, using a deviceconfigured to send information to the computer system, such as an imagecapture device, or any combination thereof.

By “data processing unit”, as used herein, is meant any hardware and/orsoftware combination that will perform the functions required of it. Forexample, any data processing unit herein may be a programmable digitalmicroprocessor such as available in the form of an electroniccontroller, mainframe, server or personal computer (desktop orportable). Where the data processing unit is programmable, suitableprogramming can be communicated from a remote location to the dataprocessing unit, or previously saved in a computer program product (suchas a portable or fixed computer readable storage medium, whethermagnetic, optical or solid state device based). Data processing unitsmay, in some instances, be specialized for particular purpose, such as,e.g., an image processing unit specialized to receive and process imagedata.

As used herein, the term “executing” is used to refer to an action thata user takes to initiate a program.

DETAILED DESCRIPTION

The present disclosure provides methods for targeting a biomedicalsystem. Aspects of the subject methods include determining thetrajectory of a targeting device using magnetic resonance imaging (MRI)of a MRI-visible style of a trajectory guide that is compatible with thetargeting device. Targeted biomedical systems may be utilized for avariety of purposes including targeted delivery of a therapeutic,holding a therapeutic device, positioning of a therapeutic device andother uses. Also provided are devices and systems that can be used inpracticing the described methods including but not limited to trajectoryguides and adjustable targeting systems, as well as non-transitorycomputer readable medium storing instructions that, when executed by acomputing device, cause a computing device to perform steps of thedescribed methods.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating un-recited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Methods

The instant disclosure provides methods for targeting a biomedicalsystem. By “biomedical system” is meant any device or system ofcomponents used in medical or therapeutic applications including but notlimited to treatment of a subject, diagnosis of a condition of asubject, biomedical research performed on a subject, and the like.Aspects of the subject methods generally, but not exclusively, includepositioning a targeting device on the surface of a subject andestablishing, aligning and/or adjusting the trajectory of the targetingdevice for one or more downstream applications that rely on thetrajectory of the targeting device for proper placement of a medicaldevice on or within the subject. In some instances, aspects of thesubject methods may also include utilizing the herein described devices,or components thereof, as a holder for therapeutic administrationdevices including but not limited to e.g., drug delivery devices, viralvector delivery devices, nanoparticle delivery devices, celladministration delivery devices, cell delivery devices, and the like.The actual configuration of a targeting device of the subject disclosurewill vary.

In some instances, a targeting device of the subject disclosure mayinclude an adjustable turret having one or more channels, the trajectoryof which is relied upon for proper positioning of a medical deviceinserted into one or more of the channels. According to someembodiments, the targeting device may be attached to the surface of asubject and adjusting the adjustable turret allows for adjusting thetrajectory of the one or more channels of the turret to better target adesired area of the subject or to avoid an obstacle within the subject.

A targeting device may be initially positioned on a tissue surface of asubject. The initial position of the targeting device on the subjectwill vary depending on a number of factors including the position of oneor more desired target areas of the subject, the position of one or moreobstacles within the subject, and the like. In some instances, thetissue surface of the subject to which the targeting device is attached,establishing the initial position, is chosen because it is the tissuesurface closest to a desired area on or into which a medical device isto be positioned. In some instances, the initial position is chosenbecause it is an accessible tissue surface, which may or may not be theclosest accessible tissue surface to a desired area on or into which amedical device is to be positioned. In some instances, the initialpositioning of the targeting device takes into account the underlyingposition of obstacles or likely underlying position of likely obstacles.For example, in some instances, the tissue surface closest to a desiredarea of a subject may not be used because doing so may require that themedical device be inserted through an obstacle or increase the chancesthat the medical device be inserted through an obstacle. In someinstances, the initial positioning may not take into account theposition of obstacles or the likely position of obstacles and thetargeting device may be positioned and any obstacles may be subsequentlyavoided during targeting, e.g., as described further herein.

In some instances, the tissue surface upon which the targeting device isinitially affixed may be first prepared for affixing the targetingdevice. Various methods of preparing the surface may be employedincluding but not limited to e.g., shaving or otherwise removing hairfrom the surface, cleaning and/or sterilizing the surface (e.g., byapplying an alcohol, an alcohol-based cleaner, an iodine based-cleaner(e.g., povidone-iodine) solution, chlorhexidine gluconate, or the like),removing one or more layers of skin from the surface, covering thesurface with a protective cover (e.g., a plastic adhesive drape), etc.In some instances, the surface may be prepared according to the currentAssociation of Surgical Technologists (AST) Standards of Practice forSkin Prep of the Surgical Patient (e.g., as available online atwww(dot)ast(dot)org). In some instances, the surface of the subject maynot be prepared or may be minimally prepared prior to placing thetargeting device including e.g., when used in an emergency applicationor field setting.

In some instances, the targeting device includes a base, eitherremovable or non-removable, that can be used to affix the targetingdevice to a tissue surface of a subject. Various methods may be employedfor attaching the base to the tissue surface of the subject. Forexample, in some instances, the base may be attached to the subjectthrough the use of one or more adhesives including but not limited tosurgical adhesives, dental acrylic, surgical/skin tape, etc. However,the use of adhesives is not necessarily required and, in some instances,the base is attached without the use of adhesive. In some instances,whether or not adhesives are used, the base may be attached to thesubject through one or more fasteners including but not limited to e.g.,sutures, buttons, staples, clips, screws, etc. As described in moredetail below, in some instances, the base of the targeting device mayinclude one or more features to facilitate attachment of the base to thesubject including but not limited to e.g., a flange, a notch, anadhesion surface, etc. In some instances, a fastener may be placedthrough such a feature including e.g., where a screw is placed through aflange to attach the base to the subject, e.g., by screwing the base toa solid tissue of the subject including e.g., cartilage, bone, etc.

The base of the device may be attached directly to the tissue surface ofthe subject or may be attached indirectly including e.g., through theuse of one or more intermediate structures including e.g., an attachmentplate, an attachment frame, etc. Intermediate structures may be used invarious situations including e.g., where the tissue to which the basewould be otherwise attached is insufficient (e.g., of insufficient size,of insufficient density or rigidity for a desired method of attachment,etc.) for attachment of the base. For example, an intermediate structure(e.g., a frame or a plate) could be used when the base is to bepositioned over a soft tissue of the subject, e.g., the eye of asubject, for device insertion into or near the soft tissue, e.g., theeye. However, such situations do not necessarily require an intermediatestructure and in some instances e.g., the base could be attacheddirectly to a small or less dense tissue of the subject including e.g.,the eye.

In some instances, the targeting device may be attached to the subjectsuch that all or nearly all components of the device remain outside thesubject. In some instances throughout the instant disclosure suchattachment may be referred to as substantially ex vivo, ex vivo and/orcompletely ex vivo. For example, the device may be attached such thatthe base is flush or nearly flush with the surface of the subject butremains substantially ex vivo or completely ex vivo. In some instances,the device may be attached such that the turret is flush or nearly flushwith the surface of the subject but remains ex vivo. Components ofcertain devices that are intentionally inserted into the subject,including e.g., a delivery device, an electrode, a camera, attachmentfasteners, etc., are generally not considered when a device is describedas substantially ex vivo and/or completely ex vivo. As such, in someinstances, a device may be simply described as ex vivo withoutaddressing the inserted component or may be specifically described as exvivo excluding the intentionally inserted component(s).

Following the attachment of the targeting device to the subject anadjustable turret of the device, and the channel(s) thereof, willgenerally have or be placed in an initial position or orientation. Forexample, in some instances, the turret may be arbitrarily positionedinitially including e.g., arbitrarily positioned perpendicular to theattachment surface. In some instances, the turret may be initiallypositioned to approximate a desired trajectory. The initial position ofthe turret generally refers to the position of the turret followingattachment to the subject but prior to any imaging-based adjustments ofthe turret.

Aspects of the instant methods include using a trajectory guide todetermine the trajectory of one or more channels of an adjustableturret. As used herein the term “trajectory guide” generally refers to adevice, described in more detail below, having one or more MRI-visiblestyles that can be inserted into one or more channels of an adjustableturret and imaged using an MRI to allow for a determination of thetrajectory of the channel to be made. Thus, MRI visualization of thestyles of a trajectory guide allow for simultaneous visualization ofboth the trajectory of the channel(s) and the target area and/or anyobstacles within or near the trajectory.

Referring now to the example presented in FIG. 1, a targeting device ofthe instant disclosure is attached to the head of a subject. Then, todetermine the trajectory of a channel within an adjustable turret (100)a style of a trajectory guide (101) is inserted into the channel and thesystem is subsequently MRI imaged. Following the imaging, the initialtrajectory (102) of the channel may be determined based on theMRI-visible style and the relative positions of the initial trajectoryand a targeted area of the subject's brain (103) may be determined. Onceany difference between the position of the trajectory and the positionof the targeted area of the brain are known, an adjustment may be madeto bring the trajectory and the targeted position of the brain intoalignment. For example, an angle adjustment of the adjustable turret(104) may be made to result in an adjusted trajectory (105) that alignsthe adjusted trajectory or more closely aligns the adjusted trajectorywith the target area.

Adjustments of a targeting device are not limited to those used toimprove the targeting of a desired area of subject. For example, asdepicted in FIG. 2, in some instances, targeting adjustments may be madeto avoid an obstacle (200). In the embodiment depicted, a desired areaof a subject's brain (201) is targeted using a targeting device havingan adjustable turret (202). The MRI-visible style (203) of a targetingguide (204) is inserted into the adjustable turret (202) and the initialtrajectory is determined (205). In the embodiment depicted, although thedetermined trajectory (205) is sufficient to target the desired area ofthe subject's brain (201) it is discovered that an obstacle (200) is inthe path of the trajectory. Accordingly, an angle adjustment of theadjustable turret is made (206) that results in a desired trajectory(207) that sufficiently targets the desired area of a subject's brain(201) while avoiding the obstacle (200). In some instances, thenecessary adjustment to achieve the desired trajectory is calculatedprior to making the adjustment, e.g., so that a minimal number ofadjustments must be made to achieve the desired trajectory, in what maybe referred to as a “calculated” or “predetermined” approach. In someinstances, the adjustment is made without calculating what adjustment isnecessary and the adjusted trajectory is analyzed to determine if itachieves a desired trajectory (e.g., targets the desired area, avoidsone or more obstacles, etc.) in what is commonly referred to as a“guess-and-check” approach.

Depicted in FIG. 1 and FIG. 2 are angle adjustments where an angleadjustment can be defined as modifying the angle of the adjustableturret relative to the long axis of the adjustable turret about a pivotpoint defined by the portion of the turret that rests within the base ofthe trajectory device. Accordingly, an angle adjustment may be measuredusing any convenient means and may be represented as the change indegrees between a starting trajectory and a modified trajectory. Usefulangle adjustments will vary and will depend on a number of factorsincluding e.g., the initial trajectory, the specific configuration ofthe targeting device, the size of the area to be targeted, etc. In someinstances, an angle adjustment may range from 0.1° or less to 60° ofmore where the maximum angle adjustment may be limited by theconfiguration of the targeting device including components or parametersof the targeting device that physically prevent greater adjustmentincluding but not limited to e.g., the size of the rounded end of theadjustable turret, the diameter of the turret, the size and shape of alocking ring, etc. In some instances, an angle adjustment may range from0.1° to 60° including but not limited to e.g., 0.1° to 55°, 0.1° to 50°,0.1° to 45°, 0.1° to 40°, 0.1° to 35°, 0.1° to 30° and the like.

As will be readily understood, adjustments of the adjustable turret arenot limited to angle adjustments and may also include, e.g., rolladjustments. As used herein, the term “roll adjustment” generally refersto rotating the adjustable turret about its long axis. While rolladjustments may not change the trajectory of a channel that is coaxialwith the adjustable turret, roll adjustments will modify the trajectoryof channels that are not coaxial with the turret. In making rolladjustments the adjustable turret may be rotated essentially any amountup to 360° including but not limited to e.g., 1°, 5°, 10°, 15°, 20°,25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, 85°, 90°,95°, 100°, 105°, 110°, 115°, 120°, 125°, 130°, 135°, 140°, 145°, 150°,155°, 160°, 165°, 170°, 175°, 180°, 185°, 190°, 195°, 200°, 205°, 210°,215°, 220°, 225°, 230°, 235°, 240°, 245°, 250°, 255°, 260°, 265°, 270°,275°, 280°, 285°, 290°, 295°, 300°, 305°, 310°, 315°, 320°, 325°, 330°,335°, 340°, 345°, 350°, 355°, and the like.

Determinations of the trajectory of a channel of an adjustable turretmade using a trajectory guide may be performed manually or automaticallywith the choice of manual or automatic adjusting being dependent on anumber of factors including but not limited to e.g., the level accuracynecessary, whether the adjustment is made manually or automatically, thenumber of adjustments likely to be performed (e.g., during a particulartargeting session), etc.

Manual determinations of the trajectory of a channel of an adjustableturret may be performed by a variety of approaches. In one embodiment,on a computer displayed or printed image of the MRI-visible style thepath of the MRI-visible style is traced to determine the trajectory. Insome instances, to determine the difference between a determinedtrajectory and a desired trajectory two lines are drawn: one defined bythe path of the MRI-visible style and the other defined by the targetand rounded end of the adjustable turret. The angle between the twolines is determined, e.g., through the use of a measuring device e.g., aprotractor, or through computer assisted measuring, e.g., softwareprogramming that measures the angle, to determine the difference betweenthe determined trajectory and the desired trajectory.

In some instances, determination of the trajectory of a channel of anadjustable turret may be automated. For example, a processor may beprogrammed to recognize the MRI-visible style from a digital MRI imageand automatically plot the trajectory of the style. The plottedtrajectory may or may not be displayed on the digital MRI image. In someinstances, the automatically plotted trajectory is displayed on adigital MRI image such that a user may make a determination as towhether the plotted trajectory achieves the desired trajectory (e.g.,targets the desired area, avoids one or more obstacles, etc.). A usermay, in some instances, provide an input to the computer system toindicate whether a desired trajectory and/or what adjustment may benecessary to achieve a desired trajectory.

In some instances, an automatically plotted trajectory is automaticallyanalyzed according to instructions programmed into the computer systemto determine whether a desired trajectory is achieved. For example, auser may provide an input representing a desired target area or one ormore obstacles to be avoided and the computer system may automaticallycalculate the trajectory and automatically determine whether thecalculated trajectory targets the desired area and/or avoids one or moreobstacles. The computer system may then, following the automaticdetermination, indicate to the user whether the calculated trajectory issufficient and, if not, the computer system may or may not be furtherprogrammed to suggest an adjustment to the trajectory sufficient totarget the desired area and/or avoid one or more obstacles. In someinstances, an automated system may be further programmed toautomatically make the necessary adjustment to achieve a desiredtrajectory.

As will be readily understood, the above described trajectorydeterminations, whether manual or automated, may be equally applied insome instances to a plurality of trajectories. Multiple trajectories maybe determined in series, i.e., one after the other, e.g., where aprocess of determining a trajectory of a channel, making an adjustmentand re-determining the trajectory is repeated, e.g., until a desiredtrajectory of the channel is achieved. In some instances, multipletrajectories of a plurality of channels may be determined in parallel,i.e., essentially simultaneously. For example, where a trajectory guidehaving a plurality of MRI-visible styles is employed, the trajectory oftwo or more channels may be determined at one time based on two or morestyles, including all of the styles, of the plurality.

In some instances, e.g., when multiple trajectories for a plurality ofchannels are determined, the targeting of a device may be modified bychoosing one channel over another based on comparing the determinedtrajectories of the channels. For example, as depicted in FIG. 3, thetrajectory (300) of a first channel (301) may be determined and that thetrajectory does not sufficiently target a desired area of a subject'sbrain (302) may be recognized. At which point a second channel (303) ofthe adjustable turret (304) may be investigated to determine if itachieves a desired trajectory to the target area. Accordingly, thetargeting guide (305) may be moved to the second channel (303) and thetrajectory (306) of the second channel may be determined. Where thesecond channel trajectory (306) is sufficient to target the desired areaof the subject's brain (302) then the second channel may be chosen andno further adjustment, e.g., of the adjustable turret, may be necessary.Alternatively, in some instances, neither channel may directly targetthe desired area and thus the channel having the trajectory that mostclosely targets the desired area may be chosen and further adjustment ofthe adjustable turret may be employed to refine the targeting.

As will be readily understood, where an adjustable turret having aplurality of channels and a trajectory guide having a plurality ofMRI-visible styles are employed, removing the style from a first channeland placing the style into a second channel, as described in the aboveembodiment, may not be necessary essentially because some or all of theplurality of channels may simultaneously contain MRI-visible stylesallowing for parallel determinations of channel trajectory to beperformed. Accordingly, in some instances, a plurality of trajectoriesmay be determined in parallel for an adjustable turret having aplurality of channels and the channel having the trajectory that besttargets the desired area may be chosen without removing and replacingthe trajectory guide.

Channel selection using an adjustable turret having a plurality ofchannels may be combined with any of the turret adjustments describedherein. For example, in some instances, a channel may be selected havinga trajectory nearest the desired trajectory and a roll adjustment may beperformed to refine the trajectory. In some instances, a channel may beselected having a trajectory nearest the desired trajectory and an angleadjustment may be performed to refine the trajectory. In some instances,a channel may be selected having a trajectory nearest the desiredtrajectory and a roll and an angle adjustment may be performed to refinethe trajectory.

Following the selection of a channel, an adjustment of the turret or acombination thereof, the selected/adjusted trajectory may be verified.Verification of the trajectory may be performed by a variety of meansincluding but not limited to e.g., determining the trajectory using atrajectory guide and plotting the trajectory on a MRI image of thesubject. The plotted trajectory may be checked to verify that thedesired area is, in fact, targeted, that the plotted trajectory avoidsany obstacles, etc. Where verification confirms that the plottedtrajectory is, in fact, a sufficient or desired trajectory then thedevice may be considered to be sufficiently targeted and downstream usesof the targeted device may be performed. Where verification is unable toconfirm that the plotted trajectory is sufficient then iterativeadjustments may be employed until a desired trajectory is achieved.

At various points within the method, the position of the adjustableturret may be locked to prevent further adjustment. For example, in someinstances, the adjustable turret may be locked in its initial position,e.g., before the initial trajectory of one or more channels isdetermined. In some instances, the position of the adjustable turret maybe locked following adjustment and/or when a trajectory of a channel ofthe adjustable turret is verified as sufficiently targeted. Locking ofthe adjustable turret will generally include placing the adjustableturret in a state that does not allow for further adjustment, eitherangle adjustment and/or roll adjustment, of the turret under normalconditions. In some instances, locking of the turret may involve the useof a locking collar, as described in more detail below, including butnot limited to e.g., a locking collar that compresses the round end ofthe adjustable turret between the base and the locking collar, thuspreventing movement.

As briefly discussed above, at various points in the herein describedmethods the MRI-visible style(s) of the trajectory guide may be removedfrom the channel(s) of the adjustable turret and/or replaced as desired.Generally, the position of the adjustable turret may be locked prior toremoving the MRI-visible style(s), e.g., to maintain a determinedtrajectory. After channel selection, turret adjustment or combinationsthereof to identify or arrive at a sufficient or desired trajectory, theMRI-visible styles will generally be removed to allow access to thetargeted channel and insertion of a device into the targeted channel,e.g., as part of a therapeutic method making use of the targetingdevice.

Therapeutic Methods

Aspects of instant methods include, in some instances, magneticresonance imaging (MRI)-assisted delivery to a desired area of a subjectusing one or more targeted channels of a targeting device as describedabove. Any desired therapeutic agent or therapeutic device may betargeted and delivered to a desired area of a subject according to themethods described herein. Non-limiting examples of agents andtherapeutic devices that may be delivered through a targeted channel asdescribed herein include but are not limited to e.g., drugs,nanoparticles, biological agents (e.g., cells, virus, etc.), electricalprobes (e.g., electrodes), thermal probes (e.g., heat probes, coldprobes, etc.), imaging devices (e.g., endoscopes, lights, etc.),surgical implements, and the like.

Subjects to which the methods of the instant disclosure are applicableinclude veterinary subjects (e.g., dogs, cats, horses, etc.) andresearch animal subjects (e.g., mice, rats, rabbits, pigs, goats, sheep,primates, etc.) as well as human subjects. The methods of the inventionare applicable to all primates, including e.g., simians. In someembodiments the methods are applied to humans. In other embodiments themethods are applied to non-human primates.

A primate is a member of the biological order Primates, the group thatcontains lemurs, the Aye-aye, lorisids, galagos, tarsiers, monkeys, andapes, with the last category including great apes. Primates are dividedinto prosimians and simians, where simians include monkeys and apes.Simians are divided into two groups: the platyrrhines or New Worldmonkeys and the catarrhine monkeys of Africa and southeastern Asia. TheNew World monkeys include the capuchin, howler and squirrel monkeys, andthe catarrhines include the Old World monkeys such as baboons andmacaques and the apes.

Any desired area of a subject may be targeted according to the methodsdescribed herein. In some instances, the desired area may a tissue,including but not limited to a tissue of endodermal origin, a tissue ofectodermal origin, a tissue mesodermal origin. Both neural andnon-neural tissues may be targeted. In some instances, neural tissues ofthe central nervous system (CNS) may be targeted including e.g., tissuesof the brain and tissues of the spinal cord. In some instances, neuraltissues of the peripheral nervous system may be targeted.

Non-neural tissues that may be targeted include but are not limited tothe skin/epidermis, tissues of the eye, tissues of the olfactory system,tissues of the ear (including inner and outer ear), tissues of the mouthand throat, non-neural tissues of the neck (including e.g., muscles,connective tissues, etc.), tissues of the heart, tissues of the lungs,tissues of stomach, tissues of the intestine (e.g., small intestine,large intestine, colon, etc.), tissues of the liver, tissues of thekidney, tissues of the endocrine system, tissues of the lymphaticsystem, tissues of the bone (including e.g., the bone marrow), tissuesof the vascular system (e.g., arteries, veins, etc.), tissues of thepancreas, tissues of the arms and legs (e.g., muscles, connectivetissues in the joints, etc.).

In some instances, the methods of the instant application may be appliedfor effective delivery/localization of an agent to a region of interestin the mammalian nervous system, including the central nervous system orthe peripheral nervous system. Essentially any region of interest of thenervous system may be targeted according to the methods as describedherein, including but not limited to e.g., the brain, the spinal cord,the spinal ganglia, etc.

In some instances, the methods of the instant application may be appliedfor effective delivery/localization of an agent to a region of interestin the mammalian brain. Essentially any region of interest of the brainmay be targeted according to the methods as described herein.

In some instances, one or more brain lobes or a particular area within abrain lobe may be targeted, including but not limited to e.g., thefrontal lobe (either the entire frontal lobe or portions thereofincluding but not limited to e.g., Superior Frontal, Rostral MiddleFrontal, Caudal Middle Frontal, Pars Opercularis, Pars Triangularis, andPars Orbitalis, Lateral Orbitofrontal, Medial Orbitofrontal, Precentral,Paracentral, Frontal Pole, combinations thereof, and the like), parietallobe (either the entire parietal lobe or portions thereof including butnot limited to e.g., Superior Parietal, Inferior Parietal,Supramarginal, Postcentral, Precuneus, combinations thereof, and thelike), temporal lobe (either the entire temporal lobe or portionsthereof including but not limited to e.g., Superior Temporal, MiddleTemporal, Inferior Temporal, Banks of the Superior Temporal Sulcus,Fusiform, Transverse Temporal, Entorhinal, Temporal Pole,Parahippocampal, combinations thereof, and the like) and occipital lobe(either the entire occipital lobe or portions thereof including but notlimited to e.g., Lateral Occipital, Lingual, Cuneus, Pericalcarine,combinations thereof, and the like).

In some instances, one or more brain structures or a particular areawithin a brain structure may be targeted including but not limited toe.g., Hindbrain structures (e.g., Myelencephalon structures (e.g.,Medulla oblongata, Medullary pyramids, Olivary body, Inferior olivarynucleus, Respiratory center, Cuneate nucleus, Gracile nucleus,Intercalated nucleus, Medullary cranial nerve nuclei, Inferiorsalivatory nucleus, Nucleus ambiguous, Dorsal nucleus of vagus nerve,Hypoglossal nucleus, Solitary nucleus, etc.), Metencephalon structures(e.g., Pons, Pontine cranial nerve nuclei, chief or pontine nucleus ofthe trigeminal nerve sensory nucleus (V), Motor nucleus for thetrigeminal nerve (V), Abducens nucleus (VI), Facial nerve nucleus (VII),vestibulocochlear nuclei (vestibular nuclei and cochlear nuclei) (VIII),Superior salivatory nucleus, Pontine tegmentum, Respiratory centres,Pneumotaxic centre, Apneustic centre, Pontine micturition center(Barrington's nucleus), Locus coeruleus, Pedunculopontine nucleus,Laterodorsal tegmental nucleus, Tegmental pontine reticular nucleus,Superior olivary complex, Paramedian pontine reticular formation,Cerebellar peduncles, Superior cerebellar peduncle, Middle cerebellarpeduncle, Inferior cerebellar peduncle, Fourth ventricle, Cerebellum,Cerebellar vermis, Cerebellar hemispheres, Anterior lobe, Posteriorlobe, Flocculonodular lobe, Cerebellar nuclei, Fastigial nucleus,Interposed nucleus, Globose nucleus, Emboliform nucleus, Dentatenucleus, etc.)), Midbrain structures (e.g., Tectum, Corporaquadrigemina, inferior colliculi, superior colliculi, Pretectum,Tegmentum, Periaqueductal gray, Parabrachial area, Medial parabrachialnucleus, Lateral parabrachial nucleus, Subparabrachial nucleus(Kölliker-Fuse nucleus), Rostral interstitial nucleus of mediallongitudinal fasciculus, Midbrain reticular formation, Dorsal raphenucleus, Red nucleus, Ventral tegmental area, Substantia nigra, Parscompacta, Pars reticulata, Interpeduncular nucleus, Cerebral peduncle,Crus cerebri, Mesencephalic cranial nerve nuclei, Oculomotor nucleus(III), Trochlear nucleus (IV), Mesencephalic duct (cerebral aqueduct,aqueduct of Sylvius), etc.), Forebrain structures (e.g., Diencephalon,Epithalamus structures (e.g., Pineal body, Habenular nuclei, Striamedullares, Taenia thalami, etc.) Third ventricle, Thalamus structures(e.g., Anterior nuclear group, Anteroventral nucleus (aka ventralanterior nucleus), Anterodorsal nucleus, Anteromedial nucleus, Medialnuclear group, Medial dorsal nucleus, Midline nuclear group, Paratenialnucleus, Reuniens nucleus, Rhomboidal nucleus, Intralaminar nucleargroup, Centromedial nucleus, Parafascicular nucleus, Paracentralnucleus, Central lateral nucleus, Central medial nucleus, Lateralnuclear group, Lateral dorsal nucleus, Lateral posterior nucleus,Pulvinar, Ventral nuclear group, Ventral anterior nucleus, Ventrallateral nucleus, Ventral posterior nucleus, Ventral posterior lateralnucleus, Ventral posterior medial nucleus, Metathalamus, Medialgeniculate body, Lateral geniculate body, Thalamic reticular nucleus,etc.), Hypothalamus structures (e.g., Anterior, Medial area, Parts ofpreoptic area, Medial preoptic nucleus, Suprachiasmatic nucleus,Paraventricular nucleus, Supraoptic nucleus (mainly), Anteriorhypothalamic nucleus, Lateral area, Parts of preoptic area, Lateralpreoptic nucleus, Anterior part of Lateral nucleus, Part of supraopticnucleus, Other nuclei of preoptic area, median preoptic nucleus,periventricular preoptic nucleus, Tuberal, Medial area, Dorsomedialhypothalamic nucleus, Ventromedial nucleus, Arcuate nucleus, Lateralarea, Tuberal part of Lateral nucleus, Lateral tuberal nuclei,Posterior, Medial area, Mammillary nuclei (part of mammillary bodies),Posterior nucleus, Lateral area, Posterior part of Lateral nucleus,Optic chiasm, Subfornical organ, Periventricular nucleus, Pituitarystalk, Tuber cinereum, Tuberal nucleus, Tuberomammillary nucleus,Tuberal region, Mammillary bodies, Mammillary nucleus, etc.),Subthalamus structures (e.g., Thalamic nucleus, Zona incerta, etc.),Pituitary gland structures (e.g., neurohypophysis, Pars intermedia(Intermediate Lobe), adenohypophysis, etc.), Telencephalon structures,white matter structures (e.g., Corona radiata, Internal capsule,External capsule, Extreme capsule, Arcuate fasciculus, Uncinatefasciculus, Perforant Path, etc.), Subcortical structures (e.g.,Hippocampus (Medial Temporal Lobe), Dentate gyrus, Cornu ammonis (CAfields), Cornu ammonis area 1, Cornu ammonis area 2, Cornu ammonis area3, Cornu ammonis area 4, Amygdala (limbic system) (limbic lobe), Centralnucleus (autonomic nervous system), Medial nucleus (accessory olfactorysystem), Cortical and basomedial nuclei (main olfactory system),Lateral[disambiguation needed] and basolateral nuclei (frontotemporalcortical system), Claustrum, Basal ganglia, Striatum, Dorsal striatum(aka neostriatum), Putamen, Caudate nucleus, Ventral striatum, Nucleusaccumbens, Olfactory tubercle, Globus pallidus (forms nucleuslentiformis with putamen), Subthalamic nucleus, Basal forebrain,Anterior perforated substance, Substantia innominata, Nucleus basalis,Diagonal band of Broca, Medial septal nuclei, etc.), Rhinencephalonstructures (e.g., Olfactory bulb, Piriform cortex, Anterior olfactorynucleus, Olfactory tract, Anterior commissure, Uncus, etc.), Cerebralcortex structures (e.g., Frontal lobe, Cortex, Primary motor cortex(Precentral gyrus, M1), Supplementary motor cortex, Premotor cortex,Prefrontal cortex, Gyri, Superior frontal gyrus, Middle frontal gyrus,Inferior frontal gyrus, Brodmann areas: 4, 6, 8, 9, 10, 11, 12, 24, 25,32, 33, 44, 45, 46, 47, Parietal lobe, Cortex, Primary somatosensorycortex (S1), Secondary somatosensory cortex (S2), Posterior parietalcortex, Gyri, Postcentral gyrus (Primary somesthetic area), Other,Precuneus, Brodmann areas 1, 2, 3 (Primary somesthetic area); 5, 7, 23,26, 29, 31, 39, 40, Occipital lobe, Cortex, Primary visual cortex (V1),V2, V3, V4, V5/MT, Gyri, Lateral occipital gyrus, Cuneus, Brodmann areas17 (V1, primary visual cortex); 18, 19, Temporal lobe, Cortex, Primaryauditory cortex (A1), secondary auditory cortex (A2), Inferior temporalcortex, Posterior inferior temporal cortex, Superior temporal gyrus,Middle temporal gyrus, Inferior temporal gyrus, Entorhinal Cortex,Perirhinal Cortex, Parahippocampal gyrus, Fusiform gyrus, Brodmannareas: 9, 20, 21, 22, 27, 34, 35, 36, 37, 38, 41, 42, Medial superiortemporal area (MST), Insular cortex, Cingulate cortex, Anteriorcingulate, Posterior cingulate, Retrosplenial cortex, Indusium griseum,Subgenual area 25, Brodmann areas 23, 24; 26, 29, 30 (retrosplenialareas); 31, 32, etc.)).

In some instances, one or more neural pathways or a particular portionof a neural pathway may be targeted including but not limited to e.g.,neural pathways of those brain lobes and structures described above,Superior Longitudinal Fasciculus, Arcuate fasciculus, Cerebral peduncle,Corpus callosum, Pyramidal or corticospinal tract, Major dopaminepathways dopamine system, Mesocortical pathway, Mesolimbic pathway,Nigrostriatal pathway, Tuberoinfundibular pathway, Serotonin Pathwaysserotonin system, Raphe Nuclei, Norepinephrine Pathways, Locuscoeruleus, etc.

In some instances, diseased and/or disease causing tissue may betargeted. Any disease and/or disease causing tissue may be targetedaccording to the instant methods including but not limited to e.g.,diseased neural tissue, solid tumors, neural or CNS tumors, and thelike. As used herein, a “CNS tumor” or “tumor of the CNS” refers to aprimary or malignant tumor of the CNS of a subject, e.g., the aberrantgrowth of cells within the CNS. The aberrantly growing cells of the CNSmay be native to the CNS or derived from other tissues.

In some instances, targeted tumors may include but are not limited toe.g., gliomas e.g., glioblastoma multiforme (GBM), astrocytoma,including fibrillary (diffuse) astrocytoma, pilocytic astrocytoma,pleomorphic xanthoastrocytoma, and brain stem glioma, oligodendroglioma,ependymoma and related paraventricular mass lesions, neuronal tumors,poorly differentiated neoplasms, including medulloblastoma, otherparenchymal tumors, including primary brain lymphoma, germ cell tumors,pineal parenchymal tumors, meningiomas, metastatic tumors,paraneoplastic syndromes, peripheral nerve sheath tumors, includingschwannoma, neurofibroma, and malignant peripheral nerve sheath tumor(malignant schwannoma).

Diseased neural tissues that may be targeted include but are not limitedto e.g., neural tissue disease due to one or more of meningitis,encephalitis, multiple sclerosis (MS), stroke, brain tumors, epilepsy,Alzheimer's disease, AIDS related dementia, Parkinson's disease.

The methods of the instant disclosure may be applied to delivery oftherapeutic agents to a targeted region of a subject, including e.g.,the brain of a subject. Agents of interest include, without limitation,proteins, drugs, antibodies, antibody fragments, immunotoxins, chemicalcompounds, protein fragments, viruses, nucleic acids (e.g., (expressionvectors, gene therapy vectors, small hairpin nucleic acids, interferingnucleic acids, aptamers, etc.) and toxins.

In some instances, the methods of the instant disclosure may include thedelivery of a gene therapy vector including but not limited to e.g.,delivery of an adenovirus (AAV) gene therapy vector.

In some instances, the methods of the instant disclosure may include thedelivery of cell therapies. As used herein, the term “cell therapy”generally includes therapies derived from the delivery of living cells,whether or not recombinantly engineered, to a subject. Useful cellsdelivered in cell therapies include but are not limited to e.g., stemcells (e.g., adult stem cells (e.g., mesenchymal stem cells, adiposestem cells, muscle satellite cells, neural stem cells, liver stem cells,hematopoietic stem cells, etc.), embryonic stem cells, inducedpluripotent stem cells (iPS), etc.) and terminally or partiallydifferentiated cell types. Useful cell types also include e.g.,engineered immune cell type such as e.g., engineered T cells.

Therapeutic agents, including cellular therapeutics, are administeredaccording to the methods described herein at any effectiveconcentration. An effective concentration of a therapeutic agent is onethat results in decreasing or increasing a particular pharmacologicaleffect. One skilled in the art would know how to determine effectiveconcentration according to methods known in the art, as well as providedherein.

Dosages of the therapeutic agents will depend upon the disease orcondition to be treated, and the individual subject's status (e.g.,species, weight, disease state, etc.) Dosages will also depend upon howthe agents are being administered where precise targeted delivery may insome instances allow for an effective dose that is smaller than asystemic dose or even a dose delivered to the general area (e.g., thebrain generally) but not specifically targeted. Effective dosages areknown in the art or can be determined empirically. Furthermore, thedosage can be adjusted according to the typical dosage for the specificdisease or condition to be treated. Often a single dose can besufficient; however, the dose can be repeated if desirable. The dosageshould not be so large as to cause adverse side effects. Generally, thedosage will vary with the age, condition, sex and extent of the diseasein the patient and can be determined by one of skill in the artaccording to routine methods (see e.g., Remington's PharmaceuticalSciences). The dosage can also be adjusted by the individual physicianin the event of any complication.

The therapeutic agent can typically include an effective amount of therespective agent in combination with a pharmaceutically acceptablecarrier and, in addition, may include other medicinal agents,pharmaceutical agents, carriers, adjuvants, diluents, etc. By“pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material may beadministered to an individual along with the selected agent withoutcausing any undesirable biological effects or interacting in adeleterious manner with any of the other components of thepharmaceutical composition in which it is contained.

For the delivery of a therapeutic agent according to the instantmethods, generally a targeting device will be targeted to a desired areaas described above using a targeting guide. Following targeting, thetargeting guide may be removed, removing the style(s) from thechannel(s) of the targeted device and replacing one or more styles witha therapeutic delivery device. Once in place within the channel of thetargeting device the therapeutic delivery device may be deployed and/oractivated, e.g., to cause the therapeutic to be released, injected,dispersed, etc. Following delivery, the delivery device may be removedor may be left in place, e.g., where a dosage protocol calls forrepeated dosing. In some instances, following one or more doses, thetargeting device may remain in place and targeting may be checked, andadjusted if necessary, using a targeting guide prior to subsequentdosing.

The subject methods are not limited to therapeutic delivery and alsoinclude targeted surgical applications such as e.g., targeted cellablation, targeted electrical stimulation, etc. In some instances, atargeting device may be applied as described herein to direct a probe,e.g., an ablation probe, an electrode, etc., to a desired area of thesubject and the probe may be activated to provide for targeted ablation(e.g., targeted neuroablation), targeted stimulation (e.g., targetedneurostimulation), etc.

The subject methods are not limited to therapeutic delivery and surgicalapplications and also include targeted diagnostics. In some instances, adiagnostic device may be deployed through a targeting device accordingto the methods as described herein for precise diagnostic protocols. Forexample, in some instances, a biopsy collection device (e.g., a fineneedle aspirate device) may be applied using a targeting system andmethod described herein to precisely target and collect a desiredbiopsy. In some instances, a diagnostic imaging instrument, e.g., anendoscope, may be applied using a targeting system and method describedherein to precisely target and collect a desired image for diagnosticpurposes. Useful endoscopes include but are not limited to e.g., thosecommercially available from Medigus Ltd (Omer, Israel) including but notlimited to e.g., the micro ScoutCam endoscope cameras.

Devices and Systems

The instant disclosure provides devices and systems useful in methodsfor targeting a biomedical device or therapy to a desired area of asubject, including devices and systems useful in practicing thosemethods as described herein. Devices described herein include trajectoryguides, adjustable turret targeting systems, and components thereof. Insome instances, the described systems may include imaging devices,biomedical systems, etc. The described devices, systems and componentsthereof may, as appropriate, be manually controlled or fully orpartially automated as described in more detail herein.

In some instances, the herein described devices, or components thereof,may serve as a holder for therapeutic administration devices includingbut not limited to e.g., drug delivery devices, viral vector deliverydevices, nanoparticle delivery devices, cell administration deliverydevices, cell delivery devices, and the like.

The instant disclosure includes trajectory guides. Trajectory guides ofthe instant disclosure will generally include at least one MRI-visiblestyle attached to base, where imaging the MRI-visible style allows forthe determination of the trajectory of a device into which theMRI-visible style is placed. MRI-visible styles of a trajectory guidemay be flexible, rigid or semi-rigid, depending on the particularcontext. A MRI visible style may, in some instances, be constructed froma tube, including flexible tubes and rigid tubing, and may have a cap atthe distal end and be open or closed at the proximal end attached to thebase. A cavity or lumen within the MRI-visible style may facilitatefilling the MRI-visible style with a contrast agent. In some instances,other configurations of an MRI-visible style may be employed includinge.g., where the MRI-visible style is constructed of an MRI-visiblematerial, including e.g., a material embedded with an MRI-contrastagent, with or without a coating.

Any convenient MRI contrast agent may find use in MRI-styles describedherein including but not limited solid (e.g., particle), liquid and gelcontrast agents. Accordingly, depending on the application, e.g.,whether the style is rigid or flexible, contrast agents used may varyand may include but are not limited to e.g., Gadolinium(III) containingMRI contrast agents (e.g., gadobenate, gadobutrol, gadocoletic acid,gadodiamide, gadofosveset, gadomelitol, gadomer 17, gadopentetate,gadopentetic acid dimeglumine, gadoterate, gadoteridol, gadoversetamide,gadoxetate, gadoxeticacid, etc.), iron oxide containing MRI contrastagents (e.g., Feridex, Resovist, Sinerem, Lumirem, PEG-fero (a.k.a.,Feruglose), etc.), iron platinum containing MRI contrast agents (e.g.,iron-platinum-based nanoparticles), manganese containing MRI contrastagents (e.g., Mn-based nanoparticles), and the like.

Referring now to FIG. 6A, in one embodiment, a trajectory guide of theinstant disclosure may include a single MRI-visible style (600) attachedto a base (601). The base of the trajectory guide will generally have asurface, e.g., a flat surface or an essentially flat surface, to whichone or more MRI-visible styles at attached. In some instances, thesurface may contain one or more holes or one or more wells into whichthe one or more styles may be inserted. In the embodiment depicted, theMRI-visible style is constructed of a tube having a cap at the distalend (602), allowing the tube to be filled with a contrast agent. As canbe seen in the cross-sectional depiction in FIG. 6B, the MRI-visiblestyle (600) has an internal lumen (603) which may be filled, e.g., withan MRI-visible contrast agent. In some instances, the base may include avoid or cavity (604) that is contiguous or confluent with the lumen ofthe MRI-visible style (603), e.g., by a direct connection of the voidand lumen or by means of an intermediate connection such as, e.g., apassage (605) as depicted in FIG. 6B.

In some instances, trajectory guides of the instant disclosure mayinclude a plurality of MRI-visible styles, e.g., as present in theembodiment depicted in FIG. 7A, which includes a base (700) and sevenMRI-visible styles (701) attached orthogonally to the base. The actualnumber of MRI-visible styles may vary depending on a number of factorsincluding but not limited to e.g., the overall size of the trajectoryguide, the dimensions of the targeting device to which the trajectoryguide is made compatible, the requirements of the desired targetingapplication and the like. As such, the number of MRI-visible styles of atargeting guide may range from 1 to 64 or more including but not limitedto e.g., 1 to 64, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 36, 1 to 30,1 to 24, 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14,1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to5, 1 to 4, 1 to 3, 2 to 64, 2 to 55, 2 to 50, 2 to 45, 2 to 40, 2 to 36,2 to 30, 2 to 24, 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15,2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2to 6, 2 to 5, 2 to 4, 5 to 64, 5 to 55, 5 to 50, 5 to 45, 5 to 40, 5 to36, 5 to 30, 5 to 24, 5 to 20, 5 to 19, 5 to 18, 5 to 17, 5 to 16, 5 to15, 5 to 14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7,10 to 64, 10 to 55, 10 to 50, 10 to 45, 10 to 40, 10 to 36, 10 to 30, 10to 24, 10 to 20, 10 to 19, 10 to 18, 10 to 17, 10 to 16, 10 to 15, 10 to14, 10 to 13, 10 to 12, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, etc.

The trajectory guide embodiment of FIG. 7A, is further depicted in FIG.7B, but with the closeable cap (703) removed. Removal of the cap (703)may allow access to a cavity in the base (704) allowing for the fillingand/or replacing of contrast agent. The cap may be affixed to the baseby any suitable means including e.g., a compression fitting or, asdepicted compatible threading in the cap (705) and base (706).Furthermore, the trajectory guide may or may not make use of one or moregaskets or O-rings, such as e.g., the gasket (707) depicted in FIG. 7Bthat provides a seal between the cap and base to prevent leakage of thecontrast agent. In some instances, component parts of a trajectory guidemay be machined such that a gaskets and/or O-rings are not necessary.

In some instances, the trajectory guide may not include a removable cap.For example, in some embodiments the trajectory guide may be configuredsuch that access to one or more lumens of one or more MRI-visible stylesis unnecessary and such configurations may not include a removable capor may not otherwise provide access to the lumen(s) of the MRI-visiblestyles. In some instances, where an MRI-visible style does not include aremovable cap on the base, access to the lumen of the MRI-visiblestyle(s) may be achieved through one or more removable caps on thedistal end of the MRI-visible styles. Depending on the particularconfiguration and the MRI contrast agent employed, in some instances,the contrast agent may need to be periodically replaced and in otherinstances the MRI-contrast agent may not need to be replaced.

The MRI-visible style(s) of a trajectory guide may vary in size alongvarious dimensions, including e.g., length, width, diameter, etc., andmay, in some instances, be configured and/or dimensioned for insertioninto a channel of an adjustable turret of a targeting device, asdescribed in more detail below. For example, the length of theMRI-style, as measured from the base of the targeting guide to thedistal end, may be essentially the same as the length of the channelinto which it is inserted or shorter. The gauge of the MRI-style may bedimensioned such that the style may be inserted into a channel anadjustable turret of a targeting device to allow for determining thetrajectory of the channel. For example, the gauge of the style may besufficiently large to conform to the trajectory of the channel but alsosufficiently small to allow for easy insertion of the style into thechannel.

As such, the dimensions of the MRI-visible style(s) of a trajectoryguide may vary. In some instances, the length of the MRI-visiblestyle(s) may range from 1 cm or less to 10 cm or more including but notlimited to e.g., 1 cm to 10 cm, 2 cm to 10 cm, 3 cm to 10 cm, 4 cm to 10cm, 5 cm to 10 cm, 1 cm to 9 cm, 1 cm to 8 cm, 1 cm to 7 cm, 1 cm to 6cm, 1 cm to 5 cm, 2 cm to 5 cm, 3 cm to 6 cm, 2 cm to 4 cm, 3 cm to 5cm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, and the like. In some instances, thegauge of the MRI-visible style(s) may range from 42 gauge or less to 6gauge or more, according to British Standard Wire Gauge (SWG)measurements, including but not limited to e.g., 42 gauge, 41 gauge, 40gauge, 39 gauge, 38 gauge, 37 gauge, 36 gauge, 35 gauge, 34 gauge, 33gauge, 32 gauge, 31 gauge, 30 gauge, 29 gauge, 28 gauge, 27 gauge, 26gauge, 25 gauge, 24 gauge, 23 gauge, 22 gauge, 21 gauge, 20 gauge, 19gauge, 18 gauge, 17 gauge, 16 gauge, 15 gauge, 14 gauge, 13 gauge, 12gauge, 11 gauge, 10 gauge, 9 gauge, 8 gauge, 7 gauge, 6 gauge, and thelike.

As described above, the trajectory guide and/or the MRI-visible style(s)thereof may be dimensioned to be compatible with an adjustable turret ofthe targeting device as described herein. Any portion or component ofthe trajectory guide and/or MRI-visible style(s) may be dimensioned tobe compatible with an adjustable turret including, e.g., the diameter orgauge of the style(s) may be dimensioned to be compatible with thechannel(s) of the adjustable turret. In some instances, the channel(s)and style(s) are configured to be compatible in length. In someinstances, the base of the trajectory guide is configured to becompatible with a surface of the adjustable turret having the openingsto the channels into which the style(s) are inserted. The turret and thetrajectory guide need not be compatibly dimensioned in all aspects and,in some instances may differ, e.g., differ in length of the styles andthe length of the channels, differ in the size of the flat surface ofthe base of the trajectory guide and the flat surface of the turrethaving the channel holes, etc. Provided it does not negatively impactthe functioning of the device any corresponding components of the turretand the trajectory guide may or may not be compatible dimensioned.

Aspects of the instant disclosure include an adjustable turret of atargeting device. In general, adjustable turrets of the instantdisclosure will include a distal end and rounded end, e.g., a sphericalor essentially spherical end. Adjustable turrets as described will alsogenerally include at least one channel running from the distal end tothe rounded end allowing for insertion of the style(s) of a trajectoryguide for targeting and insertion of one or more biomedical devices forvarious purposes including e.g., agent delivery, device delivery,imaging, etc. In some instances, an adjustable turret may have a singlechannel. In other instances, an adjustable turret may have a pluralityof channels. As such, the number of channels in an adjustable turret mayrange, e.g., from 1 to 64 or more including but not limited to e.g., 1to 64, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 1 to 36, 1 to 30, 1 to 24, 1to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4,1 to 3, 2 to 64, 2 to 55, 2 to 50, 2 to 45, 2 to 40, 2 to 36, 2 to 30, 2to 24, 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to5, 2 to 4, 5 to 64, 5 to 55, 5 to 50, 5 to 45, 5 to 40, 5 to 36, 5 to30, 5 to 24, 5 to 20, 5 to 19, 5 to 18, 5 to 17, 5 to 16, 5 to 15, 5 to14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 10 to64, 10 to 55, 10 to 50, 10 to 45, 10 to 40, 10 to 36, 10 to 30, 10 to24, 10 to 20, 10 to 19, 10 to 18, 10 to 17, 10 to 16, 10 to 15, 10 to14, 10 to 13, 10 to 12, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, etc.

The size of the rounded end of the adjustable turret may vary. Forexample, in some instances, an essentially spherical rounded end of anadjustable turret may range from 1 cm to 10 cm or more in diameterincluding but not limited to e.g., from 1 cm to 10 cm, from 2 cm to 10cm, from 3 cm to 10 cm, from 4 cm to 10 cm, from 5 cm to 10 cm, from 6cm to 10 cm, from 7 cm to 10 cm, from 8 cm to 10 cm, from 9 cm to 10 cm,from 1 cm to 9 cm, from 1 cm to 8 cm, from 1 cm to 7 cm, from 1 cm to 6cm, from 1 cm to 5 cm, from 1 cm to 4 cm, from 1 cm to 3 cm, from 1 cmto 2 cm, etc. Similarly, the length, along the long axis, of theadjustable turret will also vary where such length will also correspondor nearly correspond to the length of one or more channels of theturret. In some instances, the length of the adjustable turret may rangefrom 1 cm or less to 10 cm or more including but not limited to e.g.,from 1 cm to 10 cm, from 2 cm to 10 cm, from 3 cm to 10 cm, from 4 cm to10 cm, from 5 cm to 10 cm, from 6 cm to 10 cm, from 7 cm to 10 cm, from8 cm to 10 cm, from 9 cm to 10 cm, from 1 cm to 9 cm, from 1 cm to 8 cm,from 1 cm to 7 cm, from 1 cm to 6 cm, from 1 cm to 5 cm, from 1 cm to 4cm, from 1 cm to 3 cm, from 1 cm to 2 cm, from 2 cm to 9 cm, from 2 cmto 8 cm, from 2 cm to 7 cm, from 2 cm to 6 cm, from 2 cm to 5 cm, from 2cm to 4 cm, from 3 cm to 9 cm, from 3 cm to 8 cm, from 3 cm to 7 cm,from 3 cm to 6 cm, from 3 cm to 5 cm, from 3 cm to 4 cm, etc. Thedifference in size of the distal end of the turret and the rounded endof the turret will also vary. For example, where the rounded end isessentially spherical and the distal end is essentially cylindrical, theratio between the largest diameter at the spherical end and the diameterof the cylinder may range from more than 10:1 to than 1:1 including butnot limited to e.g., 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, andthe like.

An adjustable turret may or may not be configured to have the samenumber of channels as a corresponding trajectory guide. In addition, anadjustable turret may or may not be configured such that the channel(s)of the trajectory guide are in the same configuration as the style(s) ofthe trajectory guide. Accordingly, all, some or any one channel of anadjustable turret may be symmetrically or asymmetrically arranged withrespect to the geometric center of the distal surface of the trajectoryguide, i.e., the surface having the opening(s) to the channel(s).Accordingly, all, some or any one style of a trajectory guide may besymmetrically or asymmetrically arranged with respect to the geometriccenter of the surface to which they are attached, i.e., the surface ofthe base to which they are attached. In addition, in some instances, thearrangement of channels in an adjustable turret and the arrangement ofstyles in a corresponding trajectory guide may be configured to becompatible, whether or not the turret contains a channel or channelswhich are asymmetrically arranged or the trajectory guide contains astyle or styles which are asymmetrically arranged.

Any convenient arrangement of channels and/or styles may find use in themethods and devices of the subject disclosure. For simplicity variousnon-limiting arrangements will be described below in reference to thechannels of an adjustable turret; however, it will be readily understoodthat such arrangement may be equally applied to the styles of atrajectory guide. In embodiments having a single channel, the channelmay be arranged in the turret at any convenient location including,e.g., as depicted in FIG. 4A, the channel (400) may be positioned at thegeometric center of the turret (401), i.e., coaxial with the long axisof the turret, or the channel (402) may be positioned away from thegeometric center (403) of the turret (404), i.e., not coaxial with thelong axis of the turret.

As depicted in the non-limiting examples of FIG. 4B, in embodimentshaving a plurality of channels, two channels of the plurality may bepositioned symmetrically with respect to the geometric center of theturret (405), or may be equidistant from the geometric center of theturret but offset from the center (406), or one of the two channels maybe positioned at the center of the turret (407). As depicted in thenon-limiting examples of FIG. 4C, in embodiments having three or morechannels, three of the channels may be positioned symmetrically aboutthe geometric center of the turret (408), or asymmetrically about thegeometric center of the turret (409), or one of the three may bepositioned at the center of the turret (410).

Further exemplary depictions of possible arrangements of channels areprovided for turrets having four channels (FIG. 4D), five channels (FIG.4E) and six or more channels (FIG. 5F). It will be understood, that theexamples provided are not intended to be limiting as to the arrangementof channels, and correspondingly, to the arrangement of styles. It willbe understood that such arrangements may vary greatly and be configuredand reconfigured according to the particular desired use of the subjecttargeting system. Furthermore, although described above with regard tothe geometric center of the turret, the symmetry of the arrangement ofchannels and/or styles may be referred to relative to any othercomponent of aspect thereof of the system including e.g., anotherchannel or channels of the system, another style or styles of thesystem, any axis, plane or center of a surface of a component of thesystem, etc.

The channel(s) of the adjustable turret and/or the style(s) of thetrajectory guide may or may not be arranged parallel to the long axis ofthe turret or guide, respectively. Similarly, the channels of anadjustable turret having a plurality of channels may or may not bearranged parallel to one another and/or the styles of a trajectory guidehaving a plurality of styles may or may not be arranged parallel to oneanother. In some instances, e.g., as depicted in FIG. 5A, the channels(500) of an adjustable turret (501) may be configured parallel to thelong axis of the adjustable turret such that their trajectories remainessentially parallel. In some instances, e.g., as depicted in FIG. 5B,the channels (502) of an adjustable turret (503) may be configured suchthat they are not parallel, either to the long axis of the adjustableturret or one another or both, and their trajectories arecorrespondingly not parallel.

In some instances, a channel that is arranged within an adjustableturret not parallel to the long axis of the adjustable turret may bereferred to as flared and/or having a flared trajectory. As used hereinthe term “flared” will generally refer to a trajectory, e.g., of achannel or style, that is not parallel with the long axis of the deviceto which it is attached and having an acute angle relative to the longaxis. Components of the subject devices may be flared to variousmagnitudes, e.g., as measured by the angle of deviation from the longaxis of the device. For example in some instances a component, e.g., achannel or a style, may be flared by 1 degree or more, including but notlimited to e.g., 2 degrees or more, 3 degrees or more, 4 degrees ormore, 5 degrees or more, 6 degrees or more, 7 degrees or more, 8 degreesor more, 9 degrees or more, 10 degrees or more, 15 degrees or more, 20degrees or more, etc., but generally not flared more than about 40degrees. A device may but need not have only parallel or flaredcomponents and, as such, in some instances parallel and flaredcomponents may be combined.

Turning now to the adjustable turret depicted in FIG. 8A. In thedepicted embodiment, the adjustable turret has essentially a sphericalportion (800) and a cylindrical portion (801) and a plurality ofchannels (802) running from the flat surface on the distal end (803) ofthe cylindrical portion to the opposite end on the spherical portion.The rounded portion of the adjustable turret may or may not have a flatsurface corresponding to the point at which the channels exit theturret. For example, as depicted in FIG. 8B, in some instances, aspherical end (804) of an adjustable turret has a flat surface (805) atthat contains the channel openings (806).

In some instances, the adjustable turret may include one or more meansfor securing items inserted into one or more of the channels. Forexample, as depicted in the embodiment of FIGS. 8A and 8B, an adjustableturret may include one or more screws (807) and corresponding screwholes that extend into one or more channels such that, when tightened,the screws secure within the channel any device or other component thathas been inserted into the channel. Correspondingly, e.g., when thedevice or other component is to be removed, the screw or other fastenermay be loosened allowing removal.

In some instances, all or a portion of the adjustable turret may be madeto be MRI-visible, e.g., by embedding a contrast agent in the adjustableturret, by filling a cavity of the adjustable turret with a contrastagent, etc. In some instances, where all or a portion of the adjustableturret is made to be MRI-visible the MRI-visible portion of theadjustable turret may serve the targeting purposes of the hereindescribed MRI-visible style. For example, where the entire adjustableturret is made to be MRI-visible, visualizing the turret with an MRIdevice may allow for a determination of trajectory and/or trajectoryadjustments. In another example, where the adjustable turret includes anMRI-visible portion or an embedded MRI-visible element or a cavityfilled with a contrast agent that is parallel with one or more channelsof the adjustable turret, the MRI-visible portion or embeddedMRI-visible element or cavity filled with contrast agent may allow for adetermination of trajectory and/or trajectory adjustments. In oneembodiment, an adjustable turret as described herein may include anMRI-visible portion along the long-axis of the adjustable turretparallel with and/or adjacent to one or more channels of the adjustableturret.

MRI-visible portions along the long-axis of an adjustable turret mayvary in length and may e.g., run the entire length of the adjustableturret, less that the entire length of the adjustable turret, more thanhalf of the length of the adjustable turret, about half of the length ofthe adjustable turret, less than half the length of the adjustableturret, about 100% of the length of the adjustable turret, from about90% to about 100% of the length of the adjustable turret, from about 50%to about 100% of the length of the adjustable turret, from about 75% toabout 100% of the length of the adjustable turret, about 50% of thelength of the adjustable turret, from about 10% to about 50% of thelength of the adjustable turret, from about 25% to about 50% of thelength of the adjustable turret, from about 25% to about 75% of thelength of the adjustable turret, from about 10% to about 90% of thelength of the adjustable turret, about 10% of the length of theadjustable turret, and the like.

In some instances, an adjustable turret of the instant disclosure mayinclude an MRI-visible band. By “MRI-visible band”, as used herein, ismeant a circular or semi-circular or elliptical strip of MRI-visiblematerial (including e.g., a cavity filled with a contrast agent) thatencircles the circumference or a portion thereof (including e.g., halfof, or a majority thereof, etc.) of the adjustable turret. AnMRI-visible band may be arranged perpendicular to the long-axis of theadjustable turret. An MRI-visible band may be placed at any positionalong the long-axis of the adjustable turret. An MRI-visible band mayserver various functions in determining the position of the adjustableturret or a channel thereof or a device inserted into a channel of theadjustable turret. For example, in some instances, visualization of anMRI-visible band using an MRI imager allows for performing depthcalculations related to the position of the adjustable turret or achannel thereof or a device inserted into a channel of the adjustableturret.

As an illustration, in one embodiment, a device is inserted into achannel of an adjustable turret having an MRI-visible band and one endof the device or a specific position along the length of the device isaligned with the band. Next the adjustable turret is MRI imaged and adepth calculation is performed involving a measurement of the distancebetween a target area and the MRI-visible band. Such a depth calculationmay allow a user to determine how much of a device to insert into achannel of an adjustable turret such that the device reaches the desiredtarget area. Other configurations using an MRI-visible band for depthcalculation and other purposes will be readily apparent.

The adjustable turret of the instant devices and systems may beconfigured to be compatible with other components, e.g., for securingthe adjustable turret between adjustments and/or securing the adjustableturret to a subject. In some instances, an adjustable turret may be partof a multi-component targeting device, e.g., as depicted in FIG. 9A. Inthe embodiment of FIG. 9A, the multi-component targeting device has anadjustable turret (900), e.g., as described above, a base component(901) and a locking component (902). As can be seen in FIG. 9B, whichprovides an exploded version of the embodiment depicted in FIG. 9A, thebase component (903) may be configured to receive the rounded end of theadjustable turret (904), e.g., the rounded end of the adjustable turretmay “snap into” the base component.

The locking component (905) may be configured to allow the distal end,e.g., the cylindrical end, of the adjustable turret (906) to pass freelythrough the inner diameter of the locking component. The inner diameterof the locking component will generally be configured to be smaller thanthe diameter of the rounded end of the adjustable turret (904). Such aconfiguration of relative sizes will generally allow for the lockingcomponent to compress the rounded end of the adjustable turret when themulti-component device is assembled, e.g., by means of compatiblethreading on the exterior surface of the base (907) and interior surfacethreading on the locking component (908).

Accordingly, by turning the locking collar one direction, i.e.,tightening the locking collar, the round end of the turret is compressedbetween the locking collar and the base and adjustment of the turret isrestricted. Turning the locking collar the opposite direction, i.e.,loosening the locking collar, the compression of the round end of theturret between the locking collar and the base is released andadjustment of the turret is possible.

The locking collar need not necessarily contact the round end of theturret to effectively compress the round end of the turret and restrictadjustment. For example, in some instances, the locking collar isconfigured such that the locking collar contacts only the based and doesnot contact the round end of the adjustable turret. In such instances,turning the locking collar may compress the base, including but notlimited to e.g., a plurality of annular walls of the base as describedin more detail below, into the round end of the turret without directlycontacting the round end of the turret. As such, in some instances, thesmallest inner diameter of the locking collar may be larger than thelargest diameter of the round end of the adjustable turret. However,depending on the configuration of the base, including but not limited toe.g., the configuration of the plurality of annular walls of the base,the smallest inner diameter of the locking collar need not necessarilybe larger than the largest diameter of the round end of the adjustableturret.

In some instances, the locking collar is configured such that, when thecomponents of the systems are engaged, the locking collar does not oronly minimally impacts the maximum turret angle adjustment. Accordingly,even when the components of the device are assembled, significant angleadjustment near the otherwise maximum adjustment of the turret ispossible.

In some embodiments, the locking collar may have a lower end thatengages the base and an upper end opposite the base where the upper endhas a diameter sufficiently large such that, at maximum angleadjustments, the turret does not contact the upper end. For example, asillustrated in FIG. 14C which shows a cutaway of one embodiment of themulticomponent device, the locking collar (1400) has a lower end (1404)that engages the base (1405) and an upper end (1401) that is essentiallya ring with an inner diameter (1402) that matches or exceeds the maximumangle adjustment “X” of the turret (1403). Thus, in some instances, theupper end of the locking collar will have a diameter that is larger thanthe diameter of the lower end of the locking collar.

In some instances, the locking collar may include a flat surfacesurrounding the upper ring shaped end that is configured for turning thelocking collar, i.e., tightening and loosening the locking collar. Forexample, in the embodiment depicted in FIG. 14A, the locking collar hasa flat surface (1406) configured for turning the locking collar. Suchflat surfaces may or may not be textured. For example, in some instancesthe flat surface of the locking collar may be knurled to facilitate gripon the locking collar to facilitate turning the locking collar.Texturing and/or knurling is not limited to the flat surface of thelocking collar as described and, in some instances, any other surface ofany component of the device may be correspondingly textured and/orknurled to facilitate grip where appropriate.

The individual components of the systems may be configured such that oneor more components, including all of the components of the assembledsystem are substantially ex vivo. In some instances, the base isattached to the subject such that the base remains substantially and/orcompletely ex vivo. In some instances, the turret is attached to thesubject such that the turret remains substantially and/or completely exvivo. For example, as depicted in FIGS. 14A, and 14B which provides a 90degree rotated view of the embodiment of FIG. 14A, the assembled unit,attached to a subject at the base (1407), remains on the outside of thesubject. In some instances, the base is attached to the subject and theassembled unit is configured such that the rounded end of the turret ispositioned substantially flush with the surface of the subject to whichthe base is attached. Where the turret has a flat surface on the roundedend which contains the channel opening(s) and when the turret is alignedperpendicular to the base, the plane of the flat surface will besubstantially parallel or substantially co-planar with the surface ofthe base that interfaces with the subject.

In instances herein where a component or the system is described ascompletely or substantially ex vivo such description excludes anyfastener(s) that may be inserted into the subject to attach thecomponent or system. Likewise, descriptions of a component or the systembeing substantially or completely ex vivo will exclude situations wherethe component of system is normally ex vivo but minimally breaks theplane separating ex vivo space from in vivo space in certain adjustmentpositions. For example, in some instances, when a maximal angleadjustment is applied to the turret a small portion of the turret mayextend toward to the subject beyond the base (see e.g., FIG. 14A andFIG. 14B). However, as described herein such instances are stillconsidered to be substantially and/or completely ex vivo.

In comparison, the base of a targeting system may be configured toextend into the subject and substantially break the plane separating exvivo from in vivo. A depiction of such a situation is provide in FIG.15A and the corresponding cross section of FIG. 15B. This situationincludes a turret (1500), a locking collar (1501) and a base (1502)wherein the base includes a treaded portion that, when attached to atissue surface of the subject, extends into the subject (1503).Accordingly, the instantly described situation is not completely orsubstantially ex vivo as a portion of the base is positioned in vivo. Aconsequence of this configuration, which can be seen in the crosssection of FIG. 15B, is that at angle adjustments approaching maximum(“MAX”) the trajectory (1504) of one or more channels of the turret canbe blocked by the in vivo edge (1505) of the base. In contrast, as canbe seen in the cross section of FIG. 14C, in embodiments where the baseis substantially or completely ex vivo, interference of any edge of thebase with the trajectory of one or more channels is minimized.

In some instances, the base of a targeting system may, when the systemis assembled and attached to a subject, remain substantially orcompletely ex vivo but the round end of the turret may protrude into thesubject and thus be in vivo. In such instances, the amount that therounded end of the turret that is in vivo when assembled may varydepending on the particular turret and base configuration.

In some instances, a targeting system may include a trajectory guide anda multicomponent turret-based system that is substantially ex vivo. Insome instances, the trajectory guide of such a system may be configuredwith styles of such a length that, when the styles are inserted into thechannels of the turret the trajectory guide remains substantially orcompletely ex vivo. In some instances, the trajectory guide of such asystem may be configured with styles of such a length that, when thestyles are inserted into the channels of the turret the styles of thetrajectory guide exceed beyond the rounded end of the turret and arethus positions at least partially in vivo.

The base configured to receive the round end of the adjustable turretmay also serve to attach the assembled multi-component device to atissue surface of a subject. Any convenient means of attaching the baseto the surface of the subject may be employed and the base may beconfigured and/or modified to allow for such varied methods ofattachment. In some instances, e.g., as depicted in the embodiment ofthe base of FIG. 10, the base may include an attachment flange (1000) ora plurality of attachment flanges which may be arranged in anyconvenient orientation including but not limited to orthogonal to one ormore walls of the base. The number of flanges on a base of the subjectdevices will vary and may include but is not limited to e.g., 1 or more,2 or more, 3 or more, 4 or more, 5 or more, 6 or more, etc.

In some instances, the base may have a plurality of annular walls (1001)which collectively form a “socket” which receives the rounded end of theadjustable turret. The base may include threading on an external surfaceof the annular walls (1002) and a plurality of slots (1003) positionedbetween the annular walls. The configuration having slots between thetreaded annular walls, e.g., as depicted in FIG. 10, allow foressentially uniform compression on the rounded end of the adjustableturret to be created when the locking collar is treaded to the base andtightened. While being dimensioned to receive the spherical end of theadjustable turret, the size of the base may vary. For example, in someinstances, the area covered by the base may range from less than 1 cm²to 100 cm² or more including but not limited to e.g., 1 cm² to 100 cm²,1 cm² to 75 cm², 1 cm² to 50 cm², 1 cm² to 25 cm², 1 cm² to 20 cm², 1cm² to 15 cm², 1 cm² to 10 cm², 1 cm² to 9 cm², 1 cm² to 8 cm², 1 cm² to7 cm², 1 cm² to 6 cm², 1 cm² to 5 cm², 10 cm² to 100 cm², 25 cm² to 100cm², 50 cm² to 100 cm², 75 cm² to 100 cm², etc.

In some instances, the device or system may further include a cap tocover the device or system and/or keep any openings free of debris whennot in use. Useful caps include but are not limited to e.g., a capconfigured to cover the distal end of the turret, a cap configured coverthe base, etc. In some instances, owing to the removability of theturret from the base, e.g., by “snapping out” the turret from the base,the turret may be removed leaving an exposed hole through the center ofthe base. In some instances, the system or device may include a capconfigured to fit on top of the base when the turret is removed to coverany exposed hole within the center of the base. One embodiment of a capconfigured to cover the base when the turret is removed is depicted inFIG. 11. Caps as described herein may be held in place by any convenientmeans, including e.g., compression force, a fastener, etc. As such, acap may or may not be threaded. For example, in some instances, a cap isconfigured with internal threading compatible with the externalthreading on the annular walls of the base such that the cap may bescrewed into place, e.g., when the device is not in use.

As described in some detail above, various components of the devices andsystems described herein may be symmetrical or asymmetrical. Symmetry ofcomponents of the device and systems includes internal symmetry andsymmetry relative to another component, e.g., where two components arepositioned or attached symmetrically.

In some instances, the presence of an asymmetry in a component of adevice or system may provide a reference point during imaging to orientthe image, i.e., provide a reference point to differentiate one side ofan imaged trajectory guide from another side of the imaged trajectoryguide. Any asymmetry in the system, e.g., that can be seen visually orthat can be identified on a MRI-image, may be utilized in orienting oneor more components of the system.

For example, in some instances, the turret may contain an asymmetryincluding but not limited to e.g., a groove or indentation, to serve asa reference point. As an example, in the embodiment of a turret depictedin FIG. 12, the turret is configured with a groove (arrow) in oneposition on the turret to serve as a reference point used to orient theturret and/or identify the particular channels of the turret. Otheruseful features that may serve as an asymmetry include but are notlimited to e.g., flat sections, screw holes, screws, etc.).

In some instances, the styles of a trajectory guide may be arrangedasymmetrically such that, when viewed on an MRI-imager the asymmetry mayserve as a reference point and a means of indicating to a user or acomputer to the orientation of the targeting guide. For example, in oneembodiment, depicted in FIG. 13 the trajectory guide (1300) (pictured onthe left without styles attached and on the right with styles attached)has an asymmetrical configuration of styles. All but one style of thisasymmetric configuration corresponds to the symmetric channels of theadjustable turret (1301). The turret also contains an asymmetric groove(1302). In the embodiment depicted, the asymmetric style (1303) may beconfigured to align with the asymmetric groove (1302). Accordingly, whenthe styles of the trajectory guide are inserted into the channels andgroove of the turret the asymmetric style provides orientation of thetargeting system and identification of each channel of the turret usingMRI imaging.

Systems of the instant disclosure may further include an MRI imager. Asused herein the term “MRI imager” generally refers to any device thatfunctions using the principles of nuclear magnetic resonance imagingthat are well-known to the ordinary skilled artisan and include but arenot limited to those devices commercially available in the relevantmedical arts MRI.

Biomedical Systems

Aspects of the instant disclosure include targeted devices that mayfurther include one or more biomedical systems for delivering a targetedtherapy to a subject. The subject biomedical systems will include anysuitable device for delivering or performing any of the therapeuticmethods described above, provided the device or the operable portionthereof is able to be physically introduced through a channel of atargeting device as described herein.

In some instances, a biomedical system applied using a targeting deviceof the instant disclosure is a therapeutic delivery device, e.g., a drugdelivery device. Any suitable drug delivery device may find use in thesubject devices including but not limited to e.g., a needle, a cannula,an osmotic pump, a catheter, etc.

In some instances, a biomedical system applied using a targeting deviceof the instant disclosure is a therapy device for delivering electricalcurrent or other energy (e.g., heat) to a desired area of a subject. Anysuitable probe for therapeutic delivery may find use in the subjectdevices including but not limited to e.g., a heat probe, an electrode,etc.

In some instances, the biomedical device targeted through a channel ofthe subject targeting system may include a depth stop. As used herein,the term “depth stop” refers to any mechanism used to prevent theadverse and undesirable over-insertion of the biomedical device into thesubject. In some instances, such depth stops may be configured of asufficient diameter to prevent the biomedical device from proceedinginto the subject when the depth stop contacts the adjustable turret ofthe targeting device.

In some instances, biomedical systems of the instant disclosure includean integrated system having a MRI-imaging unit a targeting device with acorresponding biomedical therapy device. In such systems, theMRI-imaging unit, and optionally the targeting and/or delivery device,may be communicably connected to a processing device, such as aprocessor.

For example, in the embodiment depicted in FIG. 16, a system of theinstant disclosure may include a targeting device with a targeting guidein a positional relationship to an MRI-imager (“MRI”) to allow theMRI-imager to image the targeting device, targeting guide and thedesired region of treatment of the subject. The MRI-imager may furtherbe connected to a processing unit configured to receive the images fromthe MRI-imager, process the images and output the results. In someinstances, processing of the images may include determining thetrajectory of one or more channels of the targeting device anddisplaying or otherwise reporting the result to a user. In someinstances, the processor-connected MRI-imager outputs the MRI images ofthe trajectory guide but any determination of the trajectory is mademanually.

The embodiment depicted in FIG. 17, extends the embodiment of FIG. 16,where the system further include a connection between the processingunit and the targeting device. A connection between the processor andthe targeting device may be used for a variety of non-mutually exclusivepurposes. For example, in some instances, the delivery of an agent,electrical current or other therapy may be computer controlled by theprocessor such that, upon proper targeting, the computer, with orwithout further user input, triggers delivery.

In some instances, the targeting adjustments of the targeting device maybe computer controlled. For example, the targeting device may furtherinclude one or more computer controlled motors or actuators operablycoupled to the adjustable turret such that targeting adjustments may becomputer controlled. Computer controlled targeting adjustments may bedependent on user input defining the adjustment or the adjustment may beautomated based on a computer calculated trajectory and adjustment.Whether the adjustment is manual or computer determined, the describedsystems will generally include at least a user input to define thetarget region of the subject.

The processor unit of FIG. 17, include an image processing unit (IPU)configured to receive the image from the MRI-imager, a data processingunit (DPU) configured to determine the trajectory from data receivedfrom the IPU, calculate the difference between the determined trajectoryand a user inputted desired trajectory and signal any necessaryadjustment. In some instances, a signaled necessary adjustment may betransferred to a computer driver (“DRIVER”) that translates the signalto movement instructions such that either a user or motor/actuatordriven components perform the necessary adjustment of the targetingdevice. The delivery of the therapy to the subject may also be usercontrolled or may be computer controlled e.g., by one or more driversused to trigger a delivery signal.

The steps of a process for performing a herein disclosed method oftargeting using a described system to deliver a procedure to a subjectis outlined in FIG. 18. Essentially, using a herein described apparatus,the base of a targeting device is attached to a subject and the turretis snapped into the base. A targeting guide is used to insert anMRI-visible style into the turret and an MRI scan is performed. From theMRI scan the initial trajectory is determined and the system comparesthe determined trajectory to a user inputted desired trajectory. Thesystem calculates an adjustment based on the comparison and signals theadjustment to the user of a component of the system configured to makethe adjustment. The adjustment is performed, either by the user or thesystem and the adjusted trajectory is assessed. If the adjustedtrajectory is sufficient the MRI-visible style may be removed and thetreatment may be delivered. If the adjusted trajectory is insufficient,the system may loop back to the MRI scan and may repeat the trajectorydetermination and adjustment. As noted, the individual processesoutlined in FIG. 18 may, where appropriate be computer controlled.

In some instances, the components of the systems as described herein maybe connected by a wired data connection. Any suitable and appropriatewired data connection may find use in connecting the components of thedescribed systems, e.g., as described herein, including but not limitedto e.g., commercially available cables such as a USB cable, a coaxialcable, a serial cable, a C2G or Cat2 cable, a Cat5/Cat5e/Cat6/Cat6acable, a Token Ring Cable (Cat4), a VGA cable, a HDMI cable, a RCAcable, an optical fiber cable, and the like. In some instances, e.g.,where data security is less of a concern, wireless data connections maybe employed including but not limited to e.g., radio frequencyconnections (e.g., PAN/LAN/MAN/WAN wireless networking, UHF radioconnections, etc.), an infrared data transmission connection, wirelessoptical data connections, and the like.

The devices and systems of the instant disclosure may further include a“memory” that is capable of storing information such that it isaccessible and retrievable at a later date by a computer. Any convenientdata storage structure may be chosen, based on the means used to accessthe stored information. In certain aspects, the information may bestored in a “permanent memory” (i.e. memory that is not erased bytermination of the electrical supply to a computer or processor) or“non-permanent memory”. Computer hard-drive, CD-ROM, floppy disk,portable flash drive and DVD are all examples of permanent memory.Random Access Memory (RAM) is an example of non-permanent memory. A filein permanent memory may be editable and re-writable.

Substantially any circuitry can be configured to a functionalarrangement within the devices and systems for performing the methodsdisclosed herein. The hardware architecture of such circuitry, includinge.g., a specifically configured computer, is well known by a personskilled in the art, and can comprise hardware components including oneor more processors (CPU), a random-access memory (RAM), a read-onlymemory (ROM), an internal or external data storage medium (e.g., harddisk drive). Such circuitry can also comprise one or more graphic boardsfor processing and outputting graphical information to display means.The above components can be suitably interconnected via a bus within thecircuitry, e.g., inside a specific-use computer. The circuitry canfurther comprise suitable interfaces for communicating withgeneral-purpose external components such as a monitor, keyboard, mouse,network, etc. In some embodiments, the circuitry can be capable ofparallel processing or can be part of a network configured for parallelor distributive computing to increase the processing power for thepresent methods and programs. In some embodiments, the program code readout from the storage medium can be written into a memory provided in anexpanded board inserted in the circuitry, or an expanded unit connectedto the circuitry, and a CPU or the like provided in the expanded boardor expanded unit can actually perform a part or all of the operationsaccording to the instructions of the programming, so as to accomplishthe functions described.

In addition to the components of the devices and systems of the instantdisclosure, e.g., as described above, systems of the disclosure mayinclude a number of additional components, such as data output devices,e.g., monitors and/or speakers, data input devices, e.g., interfaceports, keyboards, etc., actuatable components, power sources, etc.

Computer Readable Media

The instant disclosure includes computer readable medium, includingnon-transitory computer readable medium, which stores instructions formethods described herein. Aspects of the instant disclosure includecomputer readable medium storing instructions that, when executed by acomputing device, cause the computing device to perform one or moresteps of a method as described herein.

In certain embodiments, instructions in accordance with the methodsdescribed herein can be coded onto a computer-readable medium in theform of “programming”, where the term “computer readable medium” as usedherein refers to any storage or transmission medium that participates inproviding instructions and/or data to a computer for execution and/orprocessing. Examples of storage media include a floppy disk, hard disk,optical disk, magneto-optical disk, CD-ROM, CD-ft magnetic tape,non-volatile memory card, ROM, DVD-ROM, Blue-ray disk, solid state disk,and network attached storage (NAS), whether or not such devices areinternal or external to the computer. A file containing information canbe “stored” on computer readable medium, where “storing” means recordinginformation such that it is accessible and retrievable at a later dateby a computer.

The computer-implemented method described herein can be executed usingprogramming that can be written in one or more of any number of computerprogramming languages. Such languages include, for example, Java (SunMicrosystems, Inc., Santa Clara, Calif.), Visual Basic (Microsoft Corp.,Redmond, Wash.), and C++ (AT&T Corp., Bedminster, N.J.), as well as anymany others.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A trajectory guide for magnetic resonance imaging (MRI)-assisted targeting of a desired area of a subject, comprising: a solid support comprising a flat surface; and a plurality of MRI-visible styles each comprising a lumen comprising a contrast agent, wherein each MRI-visible style of the plurality is affixed at one end to the flat surface and dimensioned for insertion into each channel of an adjustable turret comprising a plurality of channels, the adjustable turret affixed to a tissue surface of a subject thereby allowing targeting of each channel by visualizing the trajectory of each inserted MRI-visible style using an MRI imager.
 2. The trajectory guide of claim 1, wherein the plurality of MRI-visible styles comprises two or more styles that are affixed symmetrically to the flat surface with respect to the geometric center of the flat surface.
 3. The trajectory guide of claim 1, wherein the plurality of MRI-visible styles comprises at least one style that is affixed asymmetrically to the flat surface with respect to one or more styles of the plurality.
 4. The trajectory guide of claim 1, wherein the plurality of MRI-visible styles are affixed perpendicular to the flat surface.
 5. The trajectory guide of claim 1, wherein the plurality of MRI-visible styles are affixed at a flared angle to the flat surface.
 6. The trajectory guide of claim 1, wherein the solid support comprises an opening, opposite the flat surface, adjoining a void within the solid support that is contiguous with the lumens of the MRI-visible styles thereby allowing access to the void and the lumens.
 7. The trajectory guide of claim 6, further comprising a cap for closing the opening.
 8. The trajectory guide of claim 7, wherein the cap and the opening comprise compatible threading.
 9. The trajectory guide of claim 1, wherein the contrast agent comprises gadolinium.
 10. An adjustable targeting system, the system comprising: an adjustable turret comprising a distal end, a spherical end and a plurality of channels running from the distal end to the spherical end; and a base, comprising: a plurality of annular walls forming a socket dimensioned to receive the spherical end; a plurality of slots positioned between the plurality of annular walls; and a flange orthogonal to at least one of the annular walls for affixing the base to a tissue surface of a subject, wherein the channels are configured for insertion of a plurality of MRI-visible styles affixed at one end to a flat surface of a solid support of a trajectory guide into the channels.
 11. The system of claim 10, further comprising a locking collar comprising threading on an internal surface compatible with threading on the external surface of the base, wherein turning the locking collar a first direction compresses the spherical end to lock the adjustable turret in a desired trajectory and turning the locking collar a second direction decompresses the spherical end to allow for retargeting of the trajectory of the adjustable turret, and wherein turning the locking collar the first direction compresses the spherical end between the base and the locking collar to lock the adjustable turret in a desired trajectory.
 12. The system of claim 10, further comprising a locking collar comprising threading on an internal surface compatible with threading on the external surface of the base, wherein turning the locking collar a first direction compresses the spherical end to lock the adjustable turret in a desired trajectory and turning the locking collar a second direction decompresses the spherical end to allow for retargeting of the trajectory of the adjustable turret, and wherein turning the locking collar the first direction compresses the spherical end between the plurality of annular walls of the socket to lock the adjustable turret in a desired trajectory.
 13. The system of claim 10, wherein the adjustable targeting system is configured such that when affixed to the tissue surface of the subject the base and the locking collar are ex vivo.
 14. The system of claim 10, wherein the adjustable targeting system is configured such that when affixed to the tissue surface of the subject the adjustable turret is ex vivo.
 15. The system of claim 10, wherein the spherical end comprises a flat portion opposite the distal end that comprises openings to the one or more channels.
 16. The system of claim 15, wherein the spherical end and the flat portion are dimensioned such that, when inserted into the socket, the flat portion is flush with the bottom surface of the base.
 17. The system of claim 11, wherein the locking collar comprises a knurled external surface to provide grip.
 18. The system of claim 10, wherein the base comprises a plurality of flanges orthogonal to at least one of the annular walls.
 19. The system of claim 10, further comprising a trajectory guide comprising: a solid support comprising a flat surface; and a plurality of MRI-visible styles each comprising a lumen comprising a contrast agent, wherein the MRI-visible styles are affixed at one end to the flat surface and dimensioned for insertion into RA the channels of the adjustable turret affixed to a tissue surface of the subject thereby allowing targeting of the channels by visualizing the trajectory of the inserted MRI-visible styles using an MRI imager.
 20. The system of claim 19, wherein the system further comprises an MRI imager positioned to image the MRI-visible styles of the trajectory guide when the MRI-visible styles are inserted into the channels of the adjustable turret.
 21. An adjustable targeted delivery system, the system comprising: an adjustable targeting system according to claim 10; and a delivery device or electrode dimensioned for insertion into a channel of the plurality of channels of the adjustable turret.
 22. The system of claim 21, wherein the delivery device or electrode comprises a depth stop positioned at a point along the length of the delivery device or electrode to prevent inserting the delivery device into the channel past said point.
 23. An automated adjustable targeting system, the system comprising: an adjustable targeting system according to claim 10; an actuator connected to the adjustable turret and controlled by a processor programmed with instructions that, when executed by the processor, cause the processor to: determine the trajectory of a channel of the adjustable turret based on a received magnetic resonance image (MRI) of a trajectory guide MRI-visible style inserted within the channel; compare the determined trajectory to a desired user input trajectory; calculate an adjustment of the adjustable turret necessary to align the determined trajectory with the desired user input trajectory based on the comparing; and trigger the actuator to execute the adjustment thereby aligning the determined trajectory with the desired user input trajectory.
 24. The adjustable targeting system of claim 10, wherein the plurality of channels comprises at least two channels that are parallel.
 25. The adjustable targeting system of claim 10, wherein the plurality of channels comprises at least two channels that are nonparallel. 